Today there is a pressing need for a better experimental system for AIDS research, which has brought into sharp focus the shortcomings of available animal models and the practical and ethical limitations of in vivo studies of immune responses and viral pathogenesis in humans. Current studies of the human immune responses are limited to relatively restrictive in vivo experiments and several in vitro systems/assays that, although useful, lack components and the complexity of a living organism and allow only short-term studies and support responses to a few antigens. To overcome this limitation, substitute human in vivo models to small animal xenotransplantation models have been employed using human CD34+ stem cells. CD34+ hematopoietic cells obtained from marrow or blood are today in clinical use in transplantation and gene therapy studies, including ongoing attempts to expand hematopoietic stem/progenitor cells ex vivo. It was recently found that intrahepatic injection of CD34+ human cord blood cells into conditioned newborn Rag2-/-gamma-c-/- mice leads to de novo development of B, T, and dendritic cells; formation of structured primary and secondary lymphoid organs; and production of functional immune responses. This provides a valuable model to study development and function of the human immune system in vivo. In the current proposal, we show preliminary evidence that intrahepatic injection of CD34+ human cord blood cells into conditioned mice led to de novo development T- cells and monocytes. Furthermore these cells could be infected with monotropic and primary HIV-1 isolates in vitro and also be inhibited with AZT or other transcription inhibitors. Our two aims will focus on detection of HIV-1 DNA, RNA, and human surface markers in Rag2-/-gamma-c-/- infected mice in vivo (Aim I) and the effect of various HIV-1 inhibitors in these animals (Aim II). We believe that the proposed studies are novel and completion of the current work will answer some important and basic questions regarding whether this animal system is a viable option for HIV- 1 replication and drug treatment in vivo. Development of such a model would greatly contribute to the AIDS field when performing immunological, drug and vaccine studies. [unreadable] [unreadable] [unreadable]